2,3a-diazahydrindanone and 3h-pyrido-(1,2-c)pyrimidin-3-one derivatives



United States Patent Office 3,515,725 Patented June 2, 1970 US. Cl.260-251 22' Claims ABSTRACT OF THE DISCLOSURE 2,3a-diazahydrindanone and3H-pyrido-[l,2-c]pyrimidin-3-one derivatives useful as analgesics,antiphlogistics, anti-allergics and anti-inflammatory agents.

BRIEF SUMMARY OF THE INVENTION The invention relates to novelheterocyclic compounds of the formula N N-R wherein R signifieshydrogen, lower alkyl, lower alkyl bearing-one or more. substituentsselected from-the group consisting of hydroxy, halogen, amino, loweralkylamino, di-lower alkylamino and heterocyclic radicals; aryl,- arylbearing one or more substituents-selected from the group consisting ofhalogen, nitro, amino, hydroxy, lower alkyl, lower alkoxy, amino-loweralkyl,- mono-lower alkylaminolower alkyl, di-lower alkylamino-loweralkyl, trifluoromethyl, lower alkoxycarbonyl, lower acyl and loweralkanoylamido; aralkyl, 'aralkyl bearing on the aryl moiety one or moresubstituents selected from the group consist ing of halogen, nitro,amino, hydroxy, lower alkyl, lower alkoxy, amino-lower alkyl, mono-loweralkylamirio-lower alkyl, di-lower alkylamino-lower alkyl,trifluoromethyl, lower alkoxycarbonyl, lower acyl and loweralkanoyla-mido; and n signifies the value 0 or 1, andpharmaceutically-acceptable acid addition salts and quaternary saltsthereof. The compounds of Formula I are analgesics, antiphlogistics,antiallergics and anti-inflammatory agents. The invention also relatesto novel intermediates of the formula I formula ll N...

are prepared by reacting a compound of the formula NH-R NH wherein R andn are as previously described, with formaldehyde. If desired, thesubstituent R can be modified and the base thus obtained can beconverted into a pharmaceutically acceptable acid addition salt or intoa pharmaceutically acceptable quaternary salt.

As used herein, the term lower alkyl denotes a straight or branchedchain hydrocarbon of 1-7 carbon atoms, preferably of 1-4 carbon atoms,such as methyl, ethyl, propyl and isopropyl. The term lower alkoxydenotes lower alkyl ether groups in which the lower alkyl moiety is asdescribed above. The term aryl denotes phenyl and naphthyl, preferablyphenyl.

Preferred substituted aryl are: alkoxycarbonylphenyl such as,Z-methoxycarbonyl-phenyl; halophenyl, such as p-fluoro-phenyl andnitroand halo-substituted phenyl, such as 3-nitro-4-chloro-phenyl and2-nitro-4-chlorophenyl.

The term aralky denotes a straight or branched chain lower alkyl groupin which one or more of the hydrogen atoms have been replaced by an arylgroup. Benzyl and phenethyl are preferred. The term lower acyl denoteslower alkyl carbonyl groups in which lower alkyl is as described above.The term lower alkanoyl denotes an alkanoyl residue of a lowercarboxylic acid of 1-7 carbon atoms. The term halogen is to beunderstood to include chlorine, bromine, iodine and fluorine. Chlorine,bromine and fluorine are preferred. The term heterocyclic radicaldenotes a 5- and 6-membered heterocyclic radical having one or moreatoms of nitrogen, oxygen or sulfur. Examples of these are pyridyl,pyrimidyl, thienyl, thiazolyl, furyl and the like.

When n in the above Formula I signifies the value 0, the compounds are2,3 a-diazahydrindanone derivatives of the formula =0 k N R N Examplesof compounds of Formula III are:

and the like.

When n in the above Formula I signifies the value 1, the compounds are3H-pyrido-[l,2-c]pyrimidin-3-one derivav tives of the formula Examplesof compounds of Formula IV are:

Octahydro-2- (-m-nitrophenyl) -3 H-pyrido-[ 1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-Z-(p-ethoxyphenyl)-3H-pyrido-[1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-2- (m-chlorophenyl -3H-pyrido- 1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-Z- benzyl) -3H-pyrid0- l,2-c]pyrimidin-3 -one hydrochloride,

Octahydro-2- 3 ,4-dichlorophenyl) -3 H pyrido- 1,2-c]

pyrimidin-B-one hydrochloride,

Octahydro-2- (p-nitrophenyl -3-H-pyrido- [1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-Z-(o nitrophenyl)-3H-pyrido-[1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-Z- (o-methoxycarbonyl-phenyl) -3H-pyrido- 1,2-c]pyrimidin-3-one hydrochloride,

Octahydro-Z-(o-chlorophenyl)-3H-pyrido-[1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-Z- 3 -nitro-4-chlorophenyl -3 H-pyrido- [1,2-c] pyrimidin-3-one,

Octahydro-2-(4'-chloro-3'-nitrophenyl)-3H-pyrido- [1,2-c] pyrimidin-3-one hydrochloride,

Octahydro-2- 2-nitro-4'-chlorophenyl) -3 H-pyrido- [1,2-c] pyrimidin-3-one hydrochloride,

Octahydro-2-( 2',5-dichlorophenyl) -3 H-pyrido-[ 1,2-c]

pyrimidin-3-one hydrochloride,

Octahydro-2-( p-fluorophenyl) -3 I-Lpyrido- 1,2-c]

pyrimidin-3 -one,

Octahydro-2- (4-acetamido-phenyl -3'H-pyr1do- 1,2-c]

pyrimidin-3-one,

and the like.

The starting materials of Formula II wherein n signifies the value arecompounds of the formula ONT NHR

and can be prepared in accordance with the following reaction scheme:

H2NR N-COOCHzCeHb C O-NHR -O N-COOCHzCrHs NH NHR Examples of compoundsof Formula V are:

and the like.

The starting materials of Formula II wherein n signifies the value 1 arecompounds of the formula NH NHR and can be prepared in accordance withthe following. reaction scheme:

CHr-OO OH CH2 C H2-C O-NHR O NCOOCH2CeHs NH NHR Examples of compounds ofFormula VI are:

and the like.

The manufacture of the starting materials is more precisely set forth inthe examples.

The reaction of the starting materials of Formula II with formaldehydeis conveniently carried out using an aqueous formaldehyde solution andsuspending therein the starting material. If desired, the reaction canalso be carried out in the presence of an organic solvent, for example,a. lower aliphatic alcohol such as methanol or ethanol. The reactionproceeds at room temperature. However, conveniently the reaction mixtureis. heated preferably at reflux temperatures. After cooling the reactionmixture and, if desired after concentration under reduced pressure, theproduct obtained can be isolated in the usual manner, as by filtration,and purified, as by crystallization.

If desired, the substituent R of a compound thus obtained can bemodified in a further step of the process. Thus, for example, anitroaryl substituent can be reduced to the corresponding aminoarylsubstituent. Furthermore,

an aminoalkyl group can be converted to a monoor di-.

alkylamino-alkyl group, or a hydroxyalkyl group to a haloalkyl grouputilizing known procedures.

Finally, the bases obtained in accordance with the process of theinvention can, if desired, be transformed into pharmaceuticallyacceptable acid addition salts or quaternary salts. Acid addition saltscan be obtained by treatment of the bases with inorganic or organicacids, such as, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, acetic acid, citric acid, malic acid,

tartaric acid and the like. Quaternary salts can be produced in theusual manner by treatment with alkyl halides, dialkyl sulfates and thelike.

The compounds of Formula I are useful analgesics,

antiphlogistics, antiallergics and anti-inflammatory agents.

For such uses, the compounds of Formula I are formulated, usingconventional inert pharmaceutical adjuvant materials, into dosage formswhich are suitable for oral or parenteral administration. Such dosageforms include tablets, suspensions, solutions, etc. Furthermore, thecompounds of this-invention can be embodied -into,- and administered inthe form of, suitable hard or soft capsules. The identity of the inertadjuvant materials whichare used in formulating the present compoundsinto oral and parenteral dosage forms will be immediately apparent topersons skilled in the art. These adjuvant materials, either inorganicor organic in nature, include, for example, water, gelatin, lactose,starch, magnesium stearate,

talc, vegetable oils, gums, polyalkylene glycols, and the like.Moreover, preservatives, stabilizers, wetting agents, emulsifyingagents, salts for altering osmotic pressure, buffers, etc. can beincorporated, if desired, into such formulations.

The quantity of active medicamentwhich is present in any of theabove-described dosage forms is variable. It is preferred, however,toprqvide capsules or tablets containing from about 20 mg. to about 50mg. of the Formula I base or an equivalent amount of a pharmaceuticallyacceptable acid addition salt or quaternary salt thereof. For parenteraladministration, it is preferred to provide a solution containing fromabout mg./ml.

to about 20 -mg./ ml. of the Formula I base, or an equiv-" alentquantity of pharmaeeutically acceptable acid addition salt or quaternarysalt thereof. g

The frequency with which any such dosage form will be administered to apatient'w'ilbvary, depending'upon the quantity of active medicamentpresent-therein and the needs and requirements of the patienhisdiagnosed by the prescribing practitioner. Under ordinary circumstances,however, up to about 2 mg./kg. of the com pound can be administereddaily in several doses. It is to. be understood, however, that thedosages, set forth therein are exemplary.

The invention will be better understood by reference to the followingexamples which are given for illustration purposes. Temperatures, unlessotherwise stated, are expressed in degrees centigrade.

Example 1 22.5 g. of 2-(2-piperidyl) acetic acid m-nitroanilide are.dissolved in a mixture of mljof methanol and 100 ml. of 38% aqueousformaldehyde solution. The resulting.

solution is boiled at reflux for 2 hours and then con centrated underreduced pressure to about half its original volume. After dilution withwater, the reaction product is taken up in ether an d wa shed withwater. After evaporation of the ether, there remains a residue whichis.octahydro-Z-(m-nitrophenyl) 3H pyrido-[l',2-c]pyrimidin- 3-0ne, thehydrochloride of Which, after recrystallization from alcohol/ether,melts at 237-238 The 2-(2-piperidyl)acetic acid m-nitroanilide usedherein as starting material was prepared as follows:

27.7 g. of N-carbobenzoxy-Z-(2 piperidyl)acetic acid were dissolved in50 ml. of dioxane. The resulting solution was treatedwith a solution of16.6 g. of m-nitro-' aniline in 50 ml. of dioxane. The mixturethusobtained was treated at room temperature with a-solution of 24 g.-

of N,Nf-dicyclohexyl-carbodiimide in 30 ml. of dioxane.

After about 18 hours, the precipitated dicyclohexyl-ureaj was removed byfiltration, the filtrate concentrated under reduced pressure and theresidue taken up in ether. The ethereal solution was successively washedwith dilute hydrochloric acid, water, dilute sodium carbonatesolution,water and dried over magnesium sulfate. The residue remaining behindafter evaporation of the solvent under reduced pressure, was dissolvedin glacial acetic and treated under ice-cooling with 120 ml. of 33%hydrobro-..

mic acid. After about 18 hours, the solution obtained was evaporatedunder reduced pressure and the residue that remained was taken up inwater and ether. The aqueous phase, which contained the desired reactionprodnot in salt form, was Once more extracted with ether and the etherextract was discarded. After the addition of con-, centrated ammonia tothe aqueous solution, 2-(2-piperid yl)acetic acid m-nitroanilideseparatedand was taken up in methylene' chloride and washedwith'wa'terf'The 'b'ase remaining behind after the solvent was removedby distillation, yielded the corresponding hydrochloride having amelting point of 252-253z Following the procedure of Example 1, butsubstituting for the m-nitro-aniline p-ethoxy-aniline, m-chloro-aniline,benzylamine, 3,4-dichlor0-aniline, p-nitro-anilirie, o-nitroaniline,Z-methoxycarbonyl-aniline, o-chloro-aniline, 3-nitro-4-chloro-aniline,2-nitro-4-chloro-aniline, 2,5-dichloro-aniline, p-fluoro-aniline, or4-acetamido-aniline there are obtained starting materials of the formulaand end products of theformula N N-R respectively set forth in Table 1.

TABLE 1'.

Starting material End product It M.P., salt or base M.P., salt or base---O CHfi Base/ Base/1034 HCl/l97199.

01 Base/oil; HOlll9fl-191 -C H3 Base/crystalline- HOl/-l81.

' Base/100 HBr/228-. Base/138,

TABLE I-Continued Starting material End product -NH00 H, Base/205-6 1101231-2 Example 2 16 g. of a-pipercolinic acid m-trifluoromethylanilideare refluxed for 2 hours with 160 ml. of 28% formaldehyde and 2 ml. ofethanol. Upon cooling of the reaction mixture,2-(m-trifluoromethyl-phenyl)-2,3a-diazahydrindanone of melting point145l46 precipitates.

The pipecolinic m-trlfluoromethyl-anilide used herein as the startingmaterial was prepared as follows:

A solution of 21 g. of N,N-dicyclohexyl-carbodiimide in 50 ml. ofdioxane was successively treated with 16 g. of m-trifiuoromethyl-anilineand a solution of 26 g. of N-carbobenzoxya-pipecolinic acid in 50 ml. ofdioxan. The reaction mixture was allowed to stand overnight, theprecipitated N,N'-dicyclohexylurea was removed by filtration and thefiltrate was evaporated under reduced pressure. The residue wasdissolved in ether. The ethereal solution was successively washed withdilute hydrochloric acid, water, dilute sodium carbonate solution andagain with water. After evaporation of the ether, the residue wasdissolved in 50 of 33% hydrobromic acid and a-pipecolinic acidm-trifluoromethyl-anilide 'hydrobromide of melting point 260 C.crystallized out. The free base obtained from this hydrobromide in theusual manner melts at 205.

Following the procedure of Example 2, but substituting for them-trifluoromethyl-aniline 3,4-dimethoxy-aniline, p-methoxy-aniline,o-methoxycarbonyl-aniline, p-hydroxy-aniline, diethylaminoethylamine,p-fiuoro-aniline, p-chloro-aniline, p-nitro-aniline, m-nitro-anilinerespectively set forth in Table H.

(III) TABLE 11 Starting material End product B. M.P., salt or base M.P.,salt or base -o on, Base/78 Base/172 H01] -o 0H3 Base/113-114 Eel 126.

@ Base/oil HBr/ZOO".

@OH Base/230 Base/168-170 -oH,-0H,-N Base/oil 2HBr/l78.

CgHs

F HBr/2634 Jim 202203 -oi HBr/285 Base/131432",

HUI/179480.

-No, Base/103-105 Base/141442",

- 301 251-252 HUI/189490".

l N O:

- Example 3 I Tablets can be prepared in a known manner utilizing thefollowing formulation:

wherein R is benxyl; lower alkyl of 1-7 carbon atoms bearing a diloweralkylamino of 1-7 carbon atoms; phenyl; or phenyl bearing 1 to 2substituents selected from the group consisting of halogen, nitro,amino, lower alkoxy of 1-7 carbon atoms, trifluoromethyl, hydoxy,

lower alkoxy-carbonyl wherein lower alkoxy is of 1-7 carbon atoms, andlower alkanoylimido wherein alkanoyl is of 1-7 carbon atoms; and nsignifies the value 0 or 1,

and pharmaceutically acceptable acid addition and quaternary saltsthereof.

2. A compound in accordance with claim 1 wherein n is 1.

3. A compound in accordance with claim 1 wherein n is 0.

4. A compound in accordance with claim 2 wherein R is phenyl bearing oneto two substituents selected from the group consisting of halogen,nitro, amino, hydroxy,

lower alkoxy of l-7 carbon atoms, tn'fiuoromethyl, lower alkoxy carbonylwherein lower alkoxy is of 1-7 carbon atoms, and lower alkanoylimidowherein alkanoyl is of 1-7 carbon atoms.

5. A compound in accordance with claim 2 wherein R is benzyl.

6. A compound in accordance with claim 2 selected from the groupconsisting of 0ctahydro-2-(2'-nitro-4'- chlorophenyl) 3Hpyrido-[1,2-c]pyrimidin-3-one and pharmaceutically acceptable acidaddition salts thereof.

7. A compound in accordance with claim 6, octahydro- 2-(2' nitro 4chlorophenyl) 3H pyrido [1,2 c]pyrimidin-3-one.

8. A compound in accordance with claim 2 selected from the groupconsisting of octahydro-2-(3'-nitro-4- chlorophenyl) 3H pyrido[1,2-c]pyrimidin-3-one and pharmaceutically acceptable acid additionsalts thereof.

9. A compound in accordance with claim 8, octahydro- 2 (3' nitro 4'chlorophenyl) 3H pyrido [1,2- 0] pyrimidin-3-one.

10. A compound in accordance with claim 2 selected from the groupconsisting of octahydro-Z-(m-nitropheny1)-3H-pyrido-[1,2-c-]pyrimidin-3-one and pharmaceutically acceptable acidaddition salts thereof.

11. A compound in accordance with claim 10, octahydro-Z-(m-nitrophenyl)3H pyrido [1,2-c]pyrimidin- 3-one.

12. A compound in accordance with claim 2 selected from the groupconsisting of octahydro-Z-(3',4'-dichlorophenyl) 3H pyrido [1,2-c-]pyrimidin-3-one and pharmaceutically acceptable acid addition saltsthereof.

13. A compound in accordance with claim 12, octahydro-2-(3,4'dichlorophenyl) 3H pyrido [1,2- c]pyrimidin-3-one.

14. A compound in accordance with claim 2 selected from the groupconsisting of octahydro-Z-(p-nitrophenyl)- 3H pyrido[1,2-c]pyrimidin-3-one and pharmaceutically acceptable acid additionsalts thereof.

15. A compound in accordance with claim 14, octahydro-2-(p-nitrophenyl)3H pyrido [1,2-c]pyrimidin- 3-one.

16. A compound in accordance With claim 3 wherein R is phenyl bearingone to two substituents selected from the group consisting of halogen,nitro, amino, hydroxy, lower alkoxy of l-7 carbon atoms,trifluoromethyl, lower alkoxycarbonyl wherein lower alkoxy is of 1-7carbon atoms, and lower alkanoylimido wherein alkanoyl is of 17 carbonatoms.

17. A compound in accordance with claim 3 selected from the groupconsisting of 2-(o-methoxycarbonylphenyl)-2,3a-diazahydrindanone andpharmaceutically acceptable acid addition salts thereof.

18. A compound in accordance with claim 17, 2-(0-methoxy-carbonylphenyl)-2,3a-diazahydrindanone.

19. A compound in accordance with claim 3 selected from the groupconsisting of Z-(p-fluorophenyl)-2,3a-diazahydrindanone andpharmaceutically acceptable acid addition salts thereof.

20. A compound in accordance with claim 19, 2-(pfiuorophenyl -2,3a-diazahydrindanone.

21. A compound in accordance with claim 3 selected from the groupconsisting of Z-(p-nitrophenyl)-2,3a-diazahydrindanone andpharmaceutically acceptable acid addition salts thereof.

22. A compound in accordance with claim 21, 2-(pnitrophenyl-2,3a-diazahydrindanone.

References Cited Winterfeld et al., Chem. Ber. 92, 637-44 (1959).

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

2 33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3515 7z5 Dated .Tune 2 1970 Inventor-(g) Joseph Hellerbach It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 8, line 55, claim 1 1 "benxyl" should be benzzl SIGNED AND QEAIEUmans-19D (SEAL) Attest: EdwardM-HewhcrJr. mm L m.

Officer commissione 14m J Atlestmg

